1. Field of the Invention
The present invention relates to a process for producing (3R,1'S)-1-benzyl-3-(1'-N-methylamino)ethyl!pyrrolidine or (3R,1'S)-3-(1'-N-methylamino)ethyl!pyrrolidine as an intermediate for the synthesis of quinolone type anti-fungal agents such as norfloxacin, ciprofloxacin, etc.
2. Description of the Prior Art
As shown in WO 9426708, a conventional process for producing (3R,1'S)-3-(1'-N-methylamino)ethyl!pyrrolidine (14) involves subjecting optically active phenylethylamine as a starting material to formylation followed by the steps of monomethylation by reduction, addition reaction of crotonate, de-benzylation, conversion into .beta.-lactam by allylation and ring closure, ozone oxidation, reduction with sodium borohydride, mesylation, reaction with benzylamine, formation of a pyrrolidinone ring by a ring-enlarging reaction under heating and subsequent reduction with lithium aluminum hydride, and finally de-benzylation to obtain (3R,1'S)-3-(1'-N-methylamino)ethyl!pyrrolidine as a final product (see FIG. 2).
An alternative method, as described in Tetrahedron Letters, 34:7529 (1993), involves subjecting L-alanine as a starting material to t-butoxycarbonylation (conversion into BOC) followed by the steps of conversion into a .beta.-ketoester by elongation of the carbon chain, reduction of the carbonyl group, mesylation, conversion into an unsaturated ester by 1,8-diazobicyclo5,4,0!undeca-7-ene (DBU), addition of nitromethane, formation of a pyrrolidinone ring by reduction and ring closure with Raney nickel, and finally reduction with lithium aluminum hydride to obtain (3R,1'S)-3-(1'-N-methylamino)ethyl!pyrrolidine (see FIG. 3).
Furthermore, a method of preparing racemates is described in Chemical Pharmaceutical Bulletin Japan, 42: 1442 (1994) and Japanese Patent Application Laid-open Nos. 60-139830 and 279991/85, in which 4-carboxy-N-benzyl-2-pyrrolidone is acetylated and converted into an oxime, and the oxime is reduced and converted into BOC which is finally reduced with lithium aluminum hydride to obtain 3-(1'-N-methylamino)ethyl!pyrrolidine.
These methods are not industrially adequate due to the need for many steps and complicated procedures, and because expensive reagents and optically active materials are used therein.